The long term objective of this proposal is to elucidate and characterize the relationship between metabolism, oxygen content, and blood flow in the brain. Using the power and flexibility that comes with the manipulation of the mouse genome to address specific questions concerning physiologic function, transgenically altered mice expressing myoglobin in the brain will be used to study cerebral metabolism and blood flow regulation. Because the brain lacks a capacity to store oxygen and has no mechanism to facilitate the diffusion of intracellular oxygen, the expression of an oxygen buffer with the capacity to transport oxygen, such as myoglobin, may affect the way it operates under normal conditions and profoundly affect the way the brain responds to physiologic stress. Nuclear magnetic resonance (NMR) spectroscopy and state of the art NMR imaging techniques will be used as primary tools to characterize l) the functional adaptation in transgenically altered mice to the presence of brain myoglobin and 2) to assess the physiologic response, in both normal and transgenically altered mice, to various perturbations that alter the rate at which oxygen is delivered to or consumed by the brain. If the expression of myoglobin does not alter cerebral physiology, then the expressed myoglobin will be used as an intracellular oxygen probe in the brain. Combining the powers of NMR with the genetic manipulations in the mouse will afford an opportunity to critically address many of the questions regarding the regulation of blood flow in the brain and may lead to a better understanding of the clinical manifestation of stroke and other cerebral pathologies so devastating to man.